Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes. Issue 21 (1st November 2017)

• Record Type: Journal Article
• Authors: Storer, R. Ian; Pike, Andy; Swain, Nigel A.; Alexandrou, Aristos J.; Bechle, Bruce M.; Blakemore, David C.; Brown, Alan D.; Castle, Neil A.; Corbett, Matthew S.; Flanagan, Neil J.; Fengas, David; Johnson, M. Scott; Jones, Lyn H.; Marron, Brian E.; Payne, C. Elizabeth; Printzenhoff, David; Rawson, David J.; Rose, Colin R.; Ryckmans, Thomas; Sun, Jianmin; Theile, Jonathan W.; Torella, Rubben; Tseng, Elaine; Warmus, Joseph S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 21(2017)
• Page Start: 4805
• Page End: 4811
• Publication Date: 2017-11-01
• Subjects: ADME absorption, distribution, metabolism and excretion -- Clint intrinsic clearance -- Clp plasma clearance -- Clu unbound clearance -- DCM dichloromethane -- DHEP dog hepatocytes -- DLM dog liver microsomes -- DMAc dimethylacetamide -- DMF dimethylformamide -- DMSO dimethyl sulfoxide -- EP manual electrophysiology -- F bioavailability -- fu fraction unbound -- HHEP human hepatocytes -- HLM human liver microsomes -- IC50 half-maximum inhibitory concentration -- IV intravenous -- lipE lipophilic efficiency -- OATP organic anion-transporting polypeptide -- PEG polyethylene glycol -- PK pharmacokinetics -- ppb plasma protein binding -- PX PatchXpress® electrophysiology -- RHEP rat hepatocytes -- RLM rat liver microsomes -- RRCK Ralph Russ canine kidney cell line -- SAR structure activity relationship -- SNAr nucleophilic aromatic substitution -- T1/2 half-life -- TEA trimethylamine -- TEMPO (2, 2, 6, 6-Tetramethylpiperidin-1-yl)oxyl -- THF tetrahydrofuran -- TPSA topological polar surface area -- Vss apparent volume of distribution at steady state; Acid isostere -- Ion channel -- Pain -- Voltage-gated; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.056
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The discovery and selection of a highly potent and selective NaV 1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein–ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.